Heart failure is divided in different stages, which were defined by different classification systems, e.g. the International Small Animal Cardiac Health Council (ISACHC), the New York Heart Association (NYHA) functional classification systems and the currently used classification according to the Consensus Statements of the American College of Veterinary Internal Medicine (ACVIM), 2009.
Classification according to the International Small Animal Cardiac Health Council (ISACHC) System:
Class I: asymptomatic (also known as occult or preclinical)
Class IA: no evidence of compensation for underlying heart disease (no volume overload or pressure overload detected radiographically or echocardiographically)
Class IB: clinical signs of compensation for underlying heart disease (volume overload or pressure overload detected radiographically or echocardiographically)
Class II: mild to moderate heart failure with clinical signs at rest or with mild exercise (treatment required)
Class III: advanced heart failure; clinical signs of severe congestive heart failure
Class IIIA: home treatment possible
Class IIIB: requires hospitalization
New York Heart Association (NYHA) functional classification system:
Class I: describes patients with asymptomatic heart disease (e.g., chronic valvular heart disease (CVHD) is present, but no clinical signs are evident even with exercise).
Class II: describes patients with heart disease that causes clinical signs only during strenuous exercise.
Class III: describes patients with heart disease that causes clinical signs with routine daily activities or mild exercise.
Class IV: describes patients with heart disease that causes severe clinical signs even at rest.
The ACVIM system describes four basic stages of heart disease and failure:    Stage A: patients at high risk for developing heart disease but that currently have no identifiable structural disorder of the heart (e.g., every Cavalier King Charles Spaniel without a heart murmur).    Stage B: patients with structural heart disease (e.g., the typical murmur of mitral valve regurgitation is present), but that have never developed clinical signs caused by heart failure (because of important clinical implications for prognosis and treatment, the panel further subdivided Stage B into Stage B1 and B2).    Stage B1: asymptomatic patients that have no radiographic or echocardiographic evidence of cardiac remodeling in response to CVHD.    Stage B2: asymptomatic patients that have hemodynamically significant valve regurgitation, as evidenced by radiographic or echocardiographic findings of left-sided heart enlargement.    Stage C: patients with past or current clinical signs of heart failure associated with structural heart disease.    Stage D: patients with end-stage disease with clinical signs of heart failure caused by CVHD that are refractory to “standard therapy”.
The pathology of the heart begins with ISACHC Class I, NYHA Class I and ACVIM stage B2 in which cardiac murmur or cardiac chamber enlargement, but no clinical symptoms are present (ISACHC Class I or asymptomatic/occult/preclinical stage). Clinical symptoms become manifest in the course of progression of the disease (ISACHC Class II or III, NYHA class II, III or IV, ACVIM stage C and D).
Known progression of (M)MVD or CVHD/CVD or AVVI heart failure is associated with an increase of the heart size. Cardiac remodeling due to the morphologic changes within the heart is generally considered as a risk factor and is linked to worsening of pathophysiologic changes of the heart leading to heart failure. One goal of the therapy of heart failure is the reduction of the heart size and the delay of morphological changes of the heart.
A known pharmaceutically active compound to treat heart failure is pimobendan (4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone) disclosed in EP 0 008 391 and having the formula:

Pimobendan is a well-known compound for the treatment of congestive heart failure (CHF) originating for example from dilated cardiomyopathy (DCM) or mitral valve disease (MVD) in animals, especially dogs. Pimobendan is also approved as a drug product for cardiovascular treatment in humans in Japan.
Several publications disclose the use of pimobendan in the treatment of heart failure in animals, such as, for instance, the following ones.
WO 2005/092343 describes the use of PDE-III inhibitors, such as pimobendan, for the reduction of heart size of a patient suffering from heart failure without, however, mentioning patients with asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD).
Lombard and co-workers (Lombard C W et al., J Am Anim Hosp Assoc 2006, 42: 249-261) disclose the clinical efficacy of pimobendan versus benazepril for the treatment of the clinical acquired atrioventricular valvular disease in dogs.
WO 2007/054514 is directed to the use of PDE-III inhibitors, such as pimobendan, for the treatment of asymptomatic (also known as occult or preclinical) heart failure without, however, mentioning patients with asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD).
Häggström J et al. (J Vet Intern Med 2008, 22: 1124-1135) describe the effect of pimobendan or benazepril hydrochloride on survival times in dogs with clinical congestive heart failure caused by naturally occurring myxomatous mitral valve disease without, however, mentioning patients with asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD).
Summerfield N J and co-workers (Summerfield N J et al., J Vet Intern Med 2012, 26: 1337-1349) relate to a clinical study on the efficacy of pimobendan in the prevention of congestive heart failure or sudden death in Doberman Pinschers with preclinical dilated cardiomyopathy (DCM). However, they are silent about patients with asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD).
Häggström J et al. (J Vet Intern Med 2013, 27: 1452-1462) describe short-term hemodynamic and neuroendocrine effects of pimobendan and benazepril in dogs with clinical myxomatous mitral valve disease and congestive heart failure. However, they are silent about patients with asymptomatic (occult, preclinical) heart failure due to mitral valve disease (MVD).
Internet website www.epictrial.com is directed to the EPIC trial, a study to investigate the effects of pimobendan in the delay of onset of clinical symptoms of congestive heart failure due to mitral valve disease (MVD). However, at the priority dates of this patent application this trial was still ongoing and no study results were publically available.
Several other publications, however, relate to the disadvantageous cardiac effects of pimobendan treatment, such as the following ones.
Schneider P et al. (Exp Toxic Pathol 1997, 49: 217-224) describe the comparative cardiac toxicity of the IV administered pimobendan in female Beagle dogs.
Tissier R and co-workers (Tissier R et al., Cardiovascular Toxicology 2005, 5(1): 43-51) disclose adverse effects increased mitral valve regurgitation and myocardial hypertrophy in two dogs with long-term (chronic) clinical pimobendan therapy.
Amsallem E et al. (Cochrane Database Syst Rev 2005, 25: 1) found that phosphodiesterase inhibitors, such as among others pimobendan, are associated with a significant 17% increased mortality rate in human patients and in addition significantly increase cardiac death, sudden death, arrhythmias and vertigos. The authors conclude that chronic use of phosphodiesterase inhibitors should be avoided in heart failure patients.
Chetboul V and co-workers (Chetboul V et al., J Vet Intern Med 2007, 21: 742-753) show the results of a prospective, controlled, blinded and randomized study on the comparative adverse cardiac effects of pimobendan and benazepril monotherapy in dogs with mild degenerative asymptomatic mitral valve disease.
Ouellet M et al. (J Vet Intern Med 2009, 23: 258-263) describe the effect of pimobendan on echocardiographic values in dogs with asymptomatic mitral valve disease. However, this study failed to identify beneficial long-term changes in the severity of mitral regurgitation after addition of pimobendan to ACE inhibitor treatment.
The objective underlying the present invention is, therefore, to provide a medical treatment which overcomes the problems of the prior art as described above.